The major objectives of this proposal are to continue investigations on the prevention of immune rejection of islet allografts and xenografts without the continuous use of immunosuppressive drugs. Studies in our laboratory have shown that islet allograft and xenograft survival can be prolonged markedly by in vitro culture of donor islets for seven days at 24 degrees C before transplantation in conjunction with a single injection of ALS into the recipients. Recent studies indicate that megaislets can be formed in vitro from 50 rat islets and the megaislets remain functionally and morphologically intact for seven days in the presence of 95%O2. Initial studies indicate prolongation of survival of rat megaislets exposed to 95%O2 and transplanted beneath the renal capsule of diabetic mice. This model will be used to determine the optimum conditions for prevention of rejection of islet xenografts (rat to mouse); identify and characterize lymphoid cells accumulating adjacent to the megaislets; determine whether rat megaislets exposed to 95%O2 can be transplanted successfully into dogs. Pretreatment of donor mice islets with specific Ia antibodies and complement produces marked prolongation of islet allograft survival. Similar studies are in progress using specific monoclonal Ia antibodies for transplantation of rat islets into mice. Studies are in progress on the isolation and transplantation of pig islets into diabetic mice.